The role of nicotinic receptors in the pathophysiology of Alzheimer's disease

A. Nordberg, L. Nilsson-Håkansson, A. Adem, J. Hardy, I. Alafuzoff, Z. Lai, M. Herrera-Marschitz, B. Winblad

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Abstract

This chapter discusses the role of nicotinic receptors in the pathophysiology of Alzheimer's disease (AD). The nicotinic receptor binding sites in human brain have been identified and characterized by various radioligands such as the nicotinic antagonists [3H]α-bungarotoxin ([3H]Btx), [3H]tubocurarine and the agonists [3H]ACh, [3H]nicotine and [3H]methylcarbamylcholine. In rodent brain receptor binding experiments in tissue homogenates or thin tissue slices (autoradiography) have demonstrated a different localization of the antagonist [3H]Btx sites compared to the agonist sites labeled by [3H]ACh and [3H]nicotine. The difference in antagonist/agonist sites is evident at molecular level. Subtypes of nicotinic receptors are widely distributed in the human brain. Some of the nicotinic receptors are presynaptically located. In AD/SDAT brains there is a loss of high affinity to low affinity nicotinic receptors which partly might be due to an interconversion of high affinity to low affinity nicotinic sites with a simultaneous reduction in binding affinity for the low affinity sites. By lowering the affinity of the nicotinic sites, quick desensitization phenomena can be devoided and the nicotinic receptors might influence the release of acetylcholine. The finding that cholinesterase inhibitors such as THA restore the ACh release in AD/SDAT brain tissue via interaction with the nicotinic receptors open up new therapeutic strategies in the treatment of AD/SDAT and related disorders.

Original languageBritish English
Pages (from-to)353-362
Number of pages10
JournalProgress in Brain Research
Volume79
Issue numberC
DOIs
StatePublished - 1 Jan 1989

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